Calorie restriction is one of the most effective way to currently reset a large number of your aging genes. This occurs from triggering mTOR via it’s nutrient sensing capability.

⫸ In 1935, McCay et al. published the seminal paper show- ing that restricting food intake in rats to levels well below that of ad libitum feeding significantly extended life span [209]. Since then, it has been found that reducing food intake from 30 to 50% from ad libitum can extend the life span of many different species of rats and mice [210]. In addition, food restriction has been found to extend lifespan in non-mammalian species, including yeast, nematodes, and fruit flies as model animals [211–213]. Although there was no conclusive evidence at the time that food restriction could extend lifespan in primates, there was evidence that it could reduce risk factors for aging-related diseases in rhesus monkeys and humans [214, 215]. Subsequently, caloric restriction (CR) was shown to extend the lifespan of rhesus monkeys, which belong to the same primate group as humans [216]. Yet another report showed that CR improved health but did not extend lifespan [217]. Because these studies did not use the same dietary conditions, it is difficult to directly compare these results [218]. Furthermore, in primates, CR is thought to extend lifespan, depending on dietary conditions. Although this series of reports represents a landmark achievement, it is difficult to implement CR in the same way. In recent years, research has progressed in finding and evaluating compounds with similar effects to CR administered orally [219]. There are studies demonstrating the feasibility of CR in humans (for at least 2 years) and its beneficial effects on longevity risk factors and cardiometabolic risk factors [220].

Although CRs can extend human lifespan, they are also difficult to implement in humans in the long term. There- fore, there is a need to develop a method or compound that mimics or reproduces the effects of CR without limiting the amount of food. The concept of CRMs was proposed by Lane et al. in a study of 2-deoxy-d-glucose (2DG, 46) and was demonstrated in rat experiments. CRMs exhibit systemic effects of CR, including a wide range of compounds, bariatric surgery, and exercise [221].DownstreamandupstreamCRMshavebeeniden- tified. Downstream CRMs act on intracellular signaling systems and play the same role as CRs in downstream pathways: metformin (36, AMPK activation), rapamy- cin (5, mTOR inhibition), resveratrol (6, Sirtuin activa- tion), polyamines (epigenetic control), oxaloacetate (25, REDOX equilibrium). Upstream CRM, on the other hand, uses a mechanism of action that targets the energy metabolic system and sends signals upstream to mimic CR: chitosan (47, glucose reduction), acarbose (33, gly- cosidase inhibition), 2-deoxy-d-glucose (46, glycolytic inhibition), d-glucosamine (48, glycolytic regulation), d-allulose (49, glycolytic improvement), SGLT2 inhibi- tor (empagliflozin 50, canagliflozin 51, bexagliflozin 52) (Scheme 6). All upstream types of CRMs are thought to affect glucose utilization [222].

2-Deoxy-d-glucose (46, 2DG) is a glucose derivative in which the 2-position hydroxyl group of glucose is replaced by a hydrogen atom. 2DG is not metabolized by glycolysis and was the first proposed dietary restric- tion mimetic [221]. It is recognized to delay age-related dysfunction and prolong lifespan by inhibiting glycolytic activity.

d-Glucosamine (48, GlcN) is the building block of chitosan and chitin and is produced in nature by arthro- pods, fungi, and cephalopods. GlcN is produced indus- trially by hydrolyzing the exoskeleton of crustaceans, which is mostly composed of chitin. GlcN is a popular dietary supplement for the prevention and treatment of osteoarthritis in humans. Weimer et al. reported longev- ity effects of GlcN in nematodes and mice. The authors concluded that these effects were caused by impaired glucose metabolism [223]. GlcN enters cells via glucose transporters, inhibits glycolysis, and induces stored fat metabolism and mitochondrial respiration via AMPK. Increased respiration can lead to the temporary forma- tion of ROS, resulting in increased antioxidant enzyme activity, resistance to oxidative stress, and survival. Oral administration of GlcN has been reported to affect car- bohydrate metabolism and reduce body fat in rodents, contributing to increased resistance to oxidative stress and subsequent activation of AMPK. The compound has also been reported to induce autophagy in mammalian cells through a signaling pathway independent of mTOR [222]. In a clinical trial, oral administration of GlcN was used to improve vascular endothelial function by modu- lating intracellular redox status [224]. According to a large epidemiological study of consumers of various die- tary supplements, the use of GlcN was associated with a reduction in overall mortality [225]. d-Allose (49, d-Alu) is the C-3 epimer of d-fructose, a rare hexose found in limited quantities in nature. However, this compound is marketed as a zero-calorie functional sweetener and is easily produced in large quantities from d-fructose. Numerous studies have shown that d-Alu has various effects such as anti- hyperglycemic and anti-obesity. d-Alu can prolong the life span of nematodes [226]. Similar to GlcN and 2DG, d-Alu enters cells through glucose transporters, inhib- its glycolysis, and induces metabolism of stored fats and mitochondrial respiration via AMPK. Increased respiration leads to a transient upregulation of ROS production, resulting in increased antioxidant activity, resistance to oxidative stress, and viability [227]. Both d-Alu and GlcN contain a functional hexosaccharide with high safety and health benefits that are thought to extend lifespan. ⫷ [2]

◉ Until this page gets completely built out, please see the excellent review from the National Institute of Aging (Link below)

Calorie Restriction and Fasting Diets: What Do We Know?

Two excellent videos have also been linked below.